New insights into the anti-inflammatory and anti-melanoma mechanisms of action of azelaic acid and other Fusarium solani metabolites via in vitro and in silico studies.

Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds; 4-hydroxybenzaldehyde (1), 4-hydroxybenzoic acid (2), tyrosol (3), azelaic acid (4), malic acid (5), and fusaric acid (6). Fungal extract as well as its metabolites were evaluated for their anti-inflammatory and anti-hyperpigmentation potential via in vitro cyclooxygenases and tyrosinase inhibition assays, respectively. Azelaic acid (4) exhibited powerful and selective COX-2 inhibition followed by fusaric acid (6) with IC50 values (2.21 ± 0.06 and 4.81 ± 0.14 µM, respectively). As well, azelaic acid (4) had the most impressive tyrosinase inhibitory effect with IC50 value of 8.75 ± 0.18 µM compared to kojic acid (IC50 = 9.27 ± 0.19 µM). Exclusive computational studies of azelaic acid and fusaric acid with COX-2 were in good accord with the in vitro results. Interestingly, this is the first time to investigate and report the potential of compounds 3-6 to inhibit cyclooxygenase enzymes. One of the most invasive forms of skin cancer is melanoma, a molecular docking study using a set of enzymes related to melanoma suggested pirin to be therapeutic target for azelaic acid and fusaric acid as a plausible mechanism for their anti-melanoma activity.

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles.

Liver fibrosis is a disease with a great global health and economic burden. Existing data highlights itraconazole (ITRCZ) as a potentially effective anti-fibrotic therapy. However, ITRCZ effect is hindered by several limitations, such as poor solubility and bioavailability. This study aimed to formulate and optimize chitosan nanoparticles (Cht NPs) loaded with ITRCZ as a new strategy for managing liver fibrosis. ITRCZ-Cht NPs were optimized utilizing a developed 22 full factorial design. The optimized formula (F3) underwent comprehensive in vitro and in vivo characterization. In vitro assessments revealed that F3 exhibited an entrapment efficiency of 89.65% ± 0.57%, a 169.6 ± 1.77 nm particle size, and a zeta potential of +15.93 ± 0.21 mV. Furthermore, in vitro release studies indicated that the release of ITRCZ from F3 adhered closely to the first-order model, demonstrating a significant enhancement (p-value < 0.05) in cumulative release compared to plain ITRCZ suspension. This formula increased primary hepatocyte survival and decreased LDH activity in vitro. The in vivo evaluation of F3 in a rat model of liver fibrosis revealed improved liver function and structure. ITRCZ-Cht NPs displayed potent antifibrotic effects as revealed by the downregulation of TGF-ß, PDGF-BB, and TIMP-1 as well as decreased hydroxyproline content and α-SMA immunoexpression. Anti-inflammatory potential was evident by reduced TNF-α and p65 nuclear translocation. These effects were likely ascribed to the modulation of Hedgehog components SMO, GLI1, and GLI2. These findings theorize ITRCZ-Cht NPs as a promising formulation for treating liver fibrosis. However, further investigations are deemed necessary.

Combined gray scale ultrasonography and doppler diagnostic tools with strain elastography in assessment of inflammatory bowel disease in pediatrics patients.

BACKGROUND: Intestinal changes in inflammatory bowel disease (IBD) are frequently observed on ultrasound. Invasive diagnostic procedures are often employed to differentiate between the main types of IBD and detect complications. Ultrasound Strain Elastography (SE) is a promising non-invasive technique for detecting intestinal changes and assessing inflammatory activity in pediatric IBD. AIM OF THE STUDY: This research aims to evaluate the diagnostic performance of conventional ultrasound, color Doppler, and SE in assessing inflammatory bowel disease in pediatric patients, both separately and in combination as additional tools. PATIENTS AND METHODS: Forty patients (18 females and 22 males) initially diagnosed with IBD through clinical and endoscopic biopsy, along with 20 healthy controls, underwent conventional ultrasound, color Doppler, SE, and laboratory evaluations, including CBC, ESR, CRP, Fecal calprotectin, and assessment of IBD activity using PIBDAI. RESULTS: Conventional ultrasound, color Doppler, and SE significantly contributed to detecting disease activity and intestinal changes in IBD (p < 0.001; 95% CI 0.79-1.100), demonstrating better sensitivity in combination compared to each method individually. The combined approach showed 100% sensitivity, 84% specificity, 78.6% precision (Positive Predictive Value), 100% Negative Predictive Value, and an overall accuracy of 92%. CONCLUSION: The addition of Color Doppler and SE parameters to grayscale ultrasound provides diagnostic value comparable to endoscopy, histopathology, and laboratory markers in detecting inflammatory activity and intestinal changes in IBD. This combined approach can help avoid unnecessary invasive techniques for follow-up.

Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss.

BACKGROUND: The plant kingdom has long been considered a valuable source for therapeutic agents, however, some plant species still untapped and need to be phytochemically and biologically explored. Although several Atriplex species have been investigated in depth, A. leucoclada, a halophytic plant native to Saudi Arabian desert, remains to be explored for its phytochemical content and biological potentials. Herein, the current study investigated the metabolic content and the anti-inflammatory potential of A. leucoclada. METHODS: Powdered aerial parts of the plant were defatted with n-hexane then the defatted powder was extracted with 80% methanol. n-Hexane extract (ATH) was analyzed using GC-MS, while the defatted extract (ATD) was subjected to different chromatographic methods to isolate the major phytoconstituents. The structures of the purified compounds were elucidated using different spectroscopic methods including advanced NMR techniques. Anti-inflammatory activity of both extracts against COX-1 and COX-2 enzymes were examined in vitro. Molecular docking of the identified compounds into the active sites of COX-1 and COX-2 enzymes was conducted using pdb entries 6Y3C and 5IKV, respectively. RESULTS: Phytochemical investigation of ATD extract led to purification and identification of nine compounds. Interestingly, all the compounds, except for 20-hydroxy ecdysone (1), are reported for the first time from A. leucoclada, also luteolin (6) and pallidol (8) are isolated for the first time from genus Atriplex. Inhibitory activity of ATD and ATH extracts against COX-1 and COX-2 enzymes revealed concentration dependent activity of both fractions with IC50 41.22, 14.40 µg/ml for ATD and 16.74 and 5.96 µg/ml for ATH against COX-1 and COX-2, respectively. Both extracts displayed selectivity indices of 2.86 and 2.80, respectively as compared to 2.56 for Ibuprofen indicating a promising selectivity towards COX-2. Molecular docking study supported in vitro testing results, where purified metabolites showed binding affinity scores ranged from -9 to -6.4 and -8.5 to -6.6 kcal/mol for COX-1 and 2, respectively, in addition the binding energies of GC-MS detected compounds ranged from -8.9 to -5.5 and -8.3 to -5.1 kcal/mol for COX-1 and 2, respectively as compared to Ibuprofen (-6.9 and -7.5 kcal/mol, respectively), indicating high binding affinities of most of the compounds. Analysis of the binding orientations revealed variable binding patterns depending on the nature of the compounds. Our study suggested A. leucoclada as a generous source for anti-inflammatory agents.

Study protocol for Ketamine as an adjunctive therapy for major depression (2): a randomised controlled trial (KARMA-Dep [2]).

BACKGROUND: Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine's antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator. METHODS: This protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under "real world" conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness. DISCUSSION: There is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression. TRIAL REGISTRATION: EudraCT 2019-003109-92. Registered 2 October 2019. CLINICALTRIALS: gov NCT04939649. Registered 25 June 2021.

Increased susceptibility to complicated pneumonia among egyptian children with FokI (rs2228570), not TaqI (rs731236), vitamin D receptor gene polymorphism in association with vitamin D deficiency: a case-control study.

BACKGROUND: Determining a genetic contribution to the development of complicated community-acquired pneumonia in children may help understand underlying pathogenesis. We aimed to investigate the association between two vitamin D receptor (VDR) gene polymorphisms, FokI and TaqI, and susceptibility to complicated pneumonia in Egyptian children compared to uncomplicated pneumonia. Associations with 25 hydroxy-vitamin D serum level were studied. METHODS: This was a case-control study that included 320 participants divided into 2 groups: patients and controls. The patients' group included 100 children hospitalized with complicated pneumonia and 100 with uncomplicated pneumonia. 120 age and sex-matched apparently healthy children served as controls. The VDR FokI and TaqI polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. 25 hydroxy-vitamin D level was estimated in serum using ELISA. RESULTS: Regarding FokI, homozygous CC genotype was more common in complicated (52%) than uncomplicated pneumonia (28%) and controls (10%) (OR = 65; 95%CI (5.13-822.63), p < 0.001) and (OR = 4.3; 95%CI (0.7-27.16), p = 0.003), respectively. Children carrying C allele possessed 3 higher odds for complicated than uncomplicated pneumonia (OR = 3.08; 95%CI (1.33-7.14), p < 0.001). Heterozygous CT genotype increased susceptibility to complicated pneumonia (OR = 13.7; 95%CI (4.6-40.1), p < 0.001), not uncomplicated pneumonia (OR = 1.56; 95%CI (0.86-2.85), p = 0.145). Among complicated pneumonia, vitamin D level was lower in CC (6.92 ± 2.6ng/ml) than CT (9.55 ± 3.2 ng/ml) and TT genotype carriers (13.13 ± 3.6ng/ml) (p < 0.001). There was no significant difference between patients and controls as regards TaqI genotypes and alleles. CONCLUSION: In association with vitamin D deficiency, VDR gene FokI polymorphism, not TaqI, is a genetic risk factor for complicated pneumonia in Egyptian children.

Understanding the Intricacies of Delivering Compassionate Care in the Intensive Care Unit and What Hinders It: A Qualitative Study of Members of 2 Critical Care Societies.

BACKGROUND: Patient-centered care is increasing in importance especially in the post-coronavirus disease 2019 (COVID-19) pandemic era. We sought to understand factors affecting compassionate care faced by intensivists in the intensive care unit (ICU). METHODS: Using survey methodology incorporating 3 real-life case vignettes, responses were elicited to difficult ethical and moral dilemmas in the ICU setting. Members of 2 critical care societies in the United States and Europe were included in the survey. RESULTS: Responses from 323 intensivists (32% out of 1000 members who opened the initial email invitation) around the world were analyzed thematically. Conflicts between patient choices and suggested medical care, institutional/work constraints restricting compassionate care and leading to burnout, and personal variables influencing compassionate care were the themes that emerged from our investigation. The results demonstrate that intensivists have compassion for their patients and want to provide patient-centered care, but also experience stress due to their limited ability to improve their patients' conditions. CONCLUSIONS: Compassionate attitudes can be hindered by an underlying worry about the decision made by the patient and their family, a lack of confidence in making hard moral decisions, and the burdens of burnout.

Maternal COVID-19 Disease and COVID-19 Immunization.

Aim This study aimed to evaluate the immune response and vertical transmission of anti-severe acute respiratory syndrome (SARS) antibodies in vaccinated, expectant mothers infected with coronavirus disease 2019 (COVID-19) and to study the sequelae. Study design This was a retrospective study of pregnant women conducted at Bahrain Defense Force Hospital from March 2021 to September 2021. The study population was divided into two groups: group 1 was vaccinated with Sinopharm or Pfizer/BioNTech during pregnancy and never infected with COVID-19. Group 2 was unvaccinated and had been infected with COVID-19. Immune responses such as anti-nucleocapsid (anti-N) and anti-spike (anti-S) from paired samples of maternal and umbilical cord blood were measured with Elecsys immunoassay (Roche Holding AG: Basel, Switzerland) at the time of delivery. Obstetric complications such as preterm labor, preeclampsia, and stillbirth were assessed. Analysis was performed using SPSS version 26.0 (IBM Corp: Armonk, NY) and Minitab version 18 (Minitab, LLC: State College, PA). A p-value of less than 0.05 was considered statistically significant. Results The study included 90 vaccinated and 90 COVID-19-recovered pregnant women. Matched samples were available for 80 vaccinated and 74 COVID-19-recovered women. Group 1 had significantly higher levels of anti-S for both the mother and the cord blood and a significantly higher transfer ratio of anti-S. Group 2 had higher levels of anti-N. In group 1, the paired sample titer of anti-S had a weak negative correlation with maternal age whereas, in group 2, the mother's anti-N had a weak positive correlation with age. Antibodies of COVID-19-recovered mothers and cord blood had a moderate negative correlation with gestational age, except for the mother's anti-N. In group 1, the transfer ratio of anti-N and anti-S had a statistically significant association with gestational age. Preterm delivery had a high prevalence of anti-transfer ratios of <1, and delivery at >37 weeks had a high prevalence of ≥1. In group 2, 90% of preterm deliveries had transfer ratios of anti-S <1. The latency period of the COVID-19 group had a statistically significant association with the antibody transfer ratio. An interval of less than 100 days had a high prevalence in the ratio of <1. An interval of more than 100 days had a high prevalence in the ratio of ≥1. There was no significant latency period in group 1. Group 1 had a 75% prevalence of an anti-S transfer ratio ≥1 with a birth weight of >3500 g; group 2 had no significance in birth weight. We did not find significance in the sequelae of morbidities in either group. Conclusion The production of the antibody N in the COVID-19-infected and antibody S in the vaccinated pregnant women as well as the vertical transmission of antibodies was efficacious. Significant variation was found regarding maternal age in both groups. The transfer ratio of the antibodies in the vaccinated and COVID-19-recovered women was significantly higher in terms of babies of the vaccinated and the infected population. The transfer ratios were distinct according to the latency period and birth weight of the infants.

Intensivists' perceptions of what is missing in their compassionate care during interactions in the intensive care unit.

BACKGROUND: We proposed that the behaviors that demonstrate compassionate care in the intensive care unit (ICU) can be self-assessed and improved among ICU clinicians. Literature showing views of intensivists about their own compassionate care attitudes is missing. METHODS: This was an observational, prospective, cross-sectional study. We surveyed clinicians who are members of professional societies of intensive care using the modified Schwartz Center Compassionate Care Scale® (SCCCS) about their self-reported compassionate care. A modified SCCCS instrument was disseminated via an email sent to the members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine between March and June 2021. RESULTS: Three hundred twenty-three clinicians completed the survey from a cohort of 1000 members who responded (32.3% response rate). The majority (54%) of respondents were male physicians of 49 (+ - 10 SD) years of age and 19 (12 + - SD) years in practice. The mean SCCCS was 88.5 (out of 100) with an average score of 8 for each question (out of 10), showing a high self-assessed physician rating of their compassionate care in the ICU. There was a positive association with age and years in practice with a higher score, especially for women ages 30-50 years (P = 0.03). Years in practice was also independently associated with greater compassion scores (p < 0.001). Lower scores were given to behaviors that reflect understanding perspectives of families and patients and showing caring and sensitivity. In contrast, the top scores were given to behaviors that included conducting family discussions and showing respect. CONCLUSION: Physicians in the ICU self-score high in compassionate care, especially if they are more experienced, female, and older. Self-identified areas that need improvement are the humanistic qualities requiring sensitivity, such as cognitive empathy, which involves perspective-taking, reflective listening, asking open-ended questions, and understanding the patient's context and worldview. These can be addressed in further clinical and ICU quality improvement initiatives.

Characterization of Possible α-Glucosidase Inhibitors from Trigonella stellata Extract Using LC-MS and In Silico Molecular Docking.

The current study accentuates the significance of performing the multiplex approach of LC-HRESIMS, biological activity, and docking studies in drug discovery, taking into consideration a review of the literature. In this regard, the investigation of antioxidant and cytotoxic activities of Trigonella stellata collected from the Egyptian desert revealed a significant antioxidant capacity using DPPH with IC50 = 656.9 µg/mL and a moderate cytotoxicity against HepG2, MCF7, and CACO2, with IC50 values of 53.3, 48.3, and 55.8 µg/mL, respectively. The evaluation of total phenolic and flavonoid contents resulted in 32.8 mg GAE/g calculated as gallic acid equivalent and 5.6 mg RE/g calculated as rutin equivalent, respectively. Chemical profiling of T. stellata extract, using LC-HRESIMS analysis, revealed the presence of 15 metabolites, among which eleven compounds were detected for the first time in this species. Interestingly, in vitro testing of the antidiabetic activity of the alcoholic extract noted an α-glucosidase enzyme inhibitory activity (IC50 = 559.4 µg/mL) better than that of the standard Acarbose (IC50 = 799.9 µg/mL), in addition to a moderate inhibition of the α-amylase enzyme (IC50 = 0.77 µg/mL) compared to Acarbose (IC50 = 0.21 µg/mL). α-Glucosidase inhibition was also virtualized by binding interactions through the molecular docking study, presenting a high binding activity of six flavonoid glycosides, as well as the diterpenoid compound graecumoside A and the alkaloid fenugreekine. Taken together, the conglomeration of LC-HRESIMS, antidiabetic activity, and molecular docking studies shed light on T. stellata as a promising antidiabetic herb.

Omega-3 Rich Oils Attenuate ADHD-Like Behaviour Induced by Dietary Monosodium Glutamate in Rats.

<b>Background and Objective:</b> Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and cognitive dysfunction. The present study was designed to examine the possible modulatory effect of Fish, Walnuts or Fenugreek Oils against Attention Deficit Hyperactivity Disorder (ADHD)-like Behavior induced by Monosodium Glutamate (MSG) in Rats. <b>Materials and Methods:</b> Fifty weaning rats were divided into five groups, (each group contain 10 rats) as follows: Group 1: Normal control rats were fed on a balanced diet. Groups from 2-5 rats were fed on a balanced diet+MSG (0.4 g kg¹ diet), Group 2 served as a positive control group whereas group 3, 4 and 5 treated with Fish, Walnuts and Fenugreek oil, respectively, (200 mg kg¹ b.wt.) by intra-gastric tube. Biochemical and behavioural parameters were tested as well as microscopic examination of brain tissue was done. <b>Results:</b> MSG ingestion caused marked disruption in locomotors activity, memory function and brain tissue structure along with significant abnormalities in some bio-markers and reduction in the gene expression level of Bcl-2 in brain tissue. However, treatment with the tested oils showed remarkable effect by reversing the condition. <b>Conclusion:</b> Dietary supplementation with walnut; fenugreek or fish oils at the tested dose could modulate the condition of ADHD in rats.

Prenatal intake of omega-3 promotes Wnt/ß-catenin signaling pathway, and preserves integrity of the blood-brain barrier in preeclamptic rats.

BACKGROUND: Preeclampsia is a systemic, multi-organ endotheliopathy, associated with oxidative injury to the blood-brain barrier (BBB). Preeclampsia initiates a cascade of events that include neuroinflammation. Recently, it was documented that Wnt/ß-catenin signaling pathway exerts neuroprotective effects and maintain BBB integrity. We investigate the protective effect of omega-3 against neurovascular complication of preeclampsia and its relation to Wnt/ß-catenin signaling pathway. METHODOLOGY: After confirmation of day 0 pregnancy (G0), 24 adult pregnant female Wistar rats were divided into four groups control pregnant, pregnant supplemented with omega-3, preeclampsia (PE); female rats received N (ω)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day SC from day 7 to day 16 of pregnancy for induction of preeclampsia) and PE rats supplemented with omega-3. The intake of omega-3 started on day zero (0) of pregnancy until the end of the study (144 mg/kg\day orally). RESULTS: We found that omega-3 supplementation significantly improved cognitive functions and EEG amplitude, decreased blood pressure, water contents of brain tissues, sFlt-1, oxidative stress, proteinuria, and enhanced Wnt\ß-catenin proteins. Histological examination showed improved cerebral microangiopathy, increased expression of claudin-1 and -3, CD31, and VEGF in the cerebral cortical microvasculature and choroid plexus in PE rats treated with omega-3. A positive correlation between protein expression level of Wnt \ß-catenin and cognitive functions, and a negative correlation between claudin-5 relative expression, claudin-1 and -3 area % from one side and water content of the brain tissues from the other side were observed. CONCLUSION: Wnt/ß-catenin signaling pathway suspected to have an important role to improve BBB integrity. Neuroprotective, antioxidant, and anti-inflammatory effects of omega-3 were observed and can be suggested as protective supplementation for preeclampsia.

Risk of adverse outcome of COVID-19 among patients in secure psychiatric services: observational cohort study.

BACKGROUND: Secure forensic mental health services treat patients with high rates of treatment-resistant psychoses. High rates of obesity and medical comorbidities are common. Population-based studies have identified high-risk groups in the event of SARS-CoV-2 infection, including those with problems such as obesity, lung disease and immune-compromising conditions. Structured assessment tools exist to ascertain the risk of adverse outcome in the event of SARS-CoV-2 infection. AIMS: To assess risk of adverse outcome in the event of SARS-CoV-2 infection in a complete population of forensic psychiatry patients using structured assessment tools. METHOD: All patients of a national forensic mental health service (n = 141) were rated for risk of adverse outcome in the event of SARS-CoV-2 infection, using two structured tools, the COVID-Age tool and the COVID-Risk tool. RESULTS: We found high rates of relevant physical comorbidities. Mean chronological age was 45.5 years (s.d. = 11.4, median 44.1), mean score on the COVID-Age tool was 59.1 years (s.d. = 19.4, median 58.0), mean difference was 13.6 years (s.d. = 15.6), paired t = 10.9, d.f. = 140, P < 0.001. Three patients (2.1%) were chronologically over 70 years of age, compared with 43 (30.5%) with a COVID-Age over 70 (χ2 = 6.99, d.f. = 1, P = 0.008, Fisher's exact test P = 0.027). CONCLUSIONS: Patients in secure forensic psychiatric services represent a high-risk group for adverse outcomes in the event of SARS-COV-2 infection. Population-based guidance on self-isolation and other precautions based on chronological age may not be sufficient. There is an urgent need for better physical health research and treatment in this group.

Implication of JAK1/STAT3/SOCS3 Pathway in Aging of Cerebellum of Male Rat: Histological and Molecular study.

Aging causes morphological and functional changes in the cerebellum. This work aimed to demonstrate the implication of JAK1/STAT3/SOCS3 on aging-induced changes of rat cerebellum. Thirty male rats were divided into: adult (12 months), early senile (24 months) and late senile (32 months) groups. Immunohistochemical reaction of the cerebellum to GFAP and caspase-3 was assessed and the expression of JAK1, STAT3, SOCS3 proteins was also evaluated. TNFα as well as the activities of malondialdehyde (MDA) and reduced glutathione (GSH) in cerebellar tissue were also measured. The cerebellum of late senile rats revealed more degenerative changes than early senile rats in the form of increase in GFAP and caspase-3 immunoreaction. Additionally, there was decrease in JAK1and STAT3 expression in early and late senile rats and increase in SOCS3 when compare early and late senile groups with adult one. Enhancement of TNFα was noticed with aging as well as significant decrease in GSH and increase in MDA in early senile group. Moreover, late senile group revealed significant decrease in GSH and increase in MDA. It could be concluded that aging resulting in variable changes of the cerebellum as detected by morphological changes, immunohistochemical reactions of caspase-3 and GFAP and expression of JAK1/STAT3/SOCS3 proteins. Additionally, inflammatory marker TNFα and the activity of oxidative/antioxidative stress markers; malondialdehyde (MDA) and reduced glutathione (GSH) were also affected with aging.

Cimetidine a promising radio-protective agent through modulating Bax/Bcl2 ratio: An in vivo study in male rats.

Radiotherapy is one of the most effective modalities for treatment of neoplastic diseases. Radiation damage is to a large extent caused by overproduction of reactive oxygen species. To improve the therapeutic index, identifying effective substances for prevention or treatment of postirradiation intestinal and bone marrow injury should be prompted. This study was designed to evaluate the protective effects of cimetidine on the in rats exposed to γ-irradiation (5 Gy) and exploring the B-cell lymphoma 2 (Bcl2)/Bcl2 associated X (bax) pathway as a probable underlying mechanism. Eighteen adult male rats were randomly grouped into three: control, untreated irradiated rats, and irradiated rats pretreated with cimetidine. Seven days postirradiation the rats were culled, the bone marrow (BM) and jejunum tissue samples were collected for biochemical, histological, and immunohistological evaluation of BM cell count (BMCs), intestinal fibrosis, oxidative stress, tumor necrosis factor-α, Bcl2, and Bax. Cimetidine pretreatment significantly reversed the loss of BMCs, intestinal lining destruction, and fibrosis seen in the untreated irradiated rats and significantly decreased the underlying oxidative stress, inflammation, and Bax/Bcl2 ratio. There was a significant differential correlation between Bax/Bcl2 ratio, tissue oxidative stress level, and tissue injury. Cimetidine represents a very promising radioprotective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) as previously proved through different studies and adjacent healthy cells (providing radioprotection via inhibiting apoptosis) as clearly demonstrated through this study, via its antioxidant effect and subsequent regulation of type 2 apoptotic pathway through modulation of Bax/Bcl2 ratio.

A multicomponent reaction to design antimalarial pyridyl-indole derivatives: Synthesis, biological activities and molecular docking.

Using fragment-based design strategy, new pyridyl-indole hybrids 4a-y and indole intermediates 3a-e were synthesized using multicomponent one pot reaction. The synthesized compounds were subjected to screening for antimalarial activity against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum. Several compounds exhibited antimalarial activity with IC50 values in the range of 1.47-9.23 µM, and 1.16-7.66 µM, for D6 and W2 strains, respectively. Compounds 4a, 4k and 4u showed the highest selectivity index among all the tested compounds (S.I. ranged 3.8-10). Binding interactions between the active antimalarial compounds and the active site of quadruple mutant Plasmodium falciparum dihydrofolate reductase enzyme have been investigated using molecular docking analysis.

Protective effect of nebivolol on doxorubicin-induced cardiotoxicity in rats.

INTRODUCTION: The cardiotoxicity of doxorubicin is incompletely understood. We investigated the prophylactic effect of nebivolol on doxorubicin-induced cardiac toxicity. MATERIAL AND METHODS: Thirty rats were divided into a control group, doxorubicin-treated group and nebivolol + doxorubicin-treated group. The specimens were examined using H + E and Masson's trichrome, caspase 3, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and tumor necrosis factor factor-α (TNF-α). The mean area percentage of collagen fiber content, caspase-3, eNOS, iNOS and TNF-α immunoactivities was measured. RESULTS: The doxorubicin-treated group showed marked myocyte distortion and fragmentation, congestion and cytoplasmic lysis in most fibers. These changes were less intense in the nebivolol-treated group. The mean area percentage of collagen fiber in the nebivolol-treated group was non-significantly smaller (p = 0.07) than that in the doxorubicin-treated group. The expression of caspase-3 (p = 0.03), eNOS (p ≤ 0.001), iNOS (p < 0.001) and TNF-α (p = 0.003) immunoreactivity was improved in the nebivolol-treated group. CONCLUSIONS: Nebivolol exerted a significant protective effect from doxorubicin toxicity. The protective effect appears to be mediated mainly through caspase-3, eNOS, iNOS and TNF-α modulation.

Postnatal changes in the development of rat submandibular glands in offspring of diabetic mothers: Biochemical, histological and ultrastructural study.

Development and maturation of submandibular salivary glands are influenced by intrauterine diabetic environment. Several studies investigated the effects of diabetes on the salivary glands. However, the effects of maternal diabetes on the submandibular glands of the offspring was not properly examined. Therefore, the present study was designed to describe the changes in the development of the submandibular glands of the offspring of diabetic mothers. The submandibular glands of the offspring of Streptozotocin (STZ)-induced diabetic female rats were examined at two and four weeks after birth. Detection of mRNA demonstrated that maternal diabetes affects the level of different indicators. The reduction of expression of epidermal growth factor (EGF); a protein mitogen, cytokeratin 5 (CK5); an epithelial cell progenitor, CK7 and aquaporin 5 (AQP5); differentiation markers and B cell lymphoma 2 (Bcl2); an antiapoptotic marker were found. Increase in Bcl2-associated X protein (Bax); an apoptotic marker was detected. These changes indicate their effects on saliva secretion, glands tumorigenesis, growth of normal oral flora and oral microbes, with decreased protein synthesis and production of xerostomia and dental caries. Loss of normal glandular architecture, significant increase in fibrosis, by the detection of collagen fibers, and stagnation of secretory granules were found with atrophic changes in the acinar cells. Marked defect of polysaccharides in the acinar cells, denoting functional changes, was manifested by significant reduction of the intensity of periodic acid-Schiff (PAS) reaction. The positive immunoreactivity of caspase-3, denoting cellular apoptosis, and minimal reaction of alpha-smooth muscle actin (α SMA) and proliferating cell nuclear antigen (PCNA) were evident in the offspring of diabetic mothers. We conclude that maternal diabetes produces degenerative effects in the structure and function of the submandibular salivary glands of the offspring, reflecting possible influences on their secretory activity affecting oral and digestive health.

Age-associated functional morphology of thyroid and its impact on the expression of vimentin, cytokeratins and VEGF. The role of nigella in refinement.

INTRODUCTION: Aging causes morphological and functional changes in the thyroid gland. Free radicals play a key role in the pathology of normal aging. Vimentin and cytokeratin are cytoskeletal intermediate filaments that are often used as indirect indices of tissue injury. The aim of the study was to clarify the age-related alterations in the structure and function of the thyroid gland. The relationship between oxidative/antioxidative stress markers and cytoskeletal intermediate filaments (vimentin and cytokeratin) and oxidative/antioxidative stress markers as well as vascular endothelial growth factor (VEGF) during aging were elucidated. Finally, the role of Nigella sativa (NS) oil in ameliorating age-related alterations of the structure and function of the thyroid gland was studied. MATERIAL AND METHODS: Thirty Sprague-Dawley albino rats were divided into five groups: young adult control, young adult NS-treated, late adult control, late adult NS-treated, and senile. The age of young adult, late adult, and senile rats was nearly 7, 18 and 22 months, respectively. NS oil was added to food pellets and was administered at a daily dose of 0.1 g/kg body weight for one month. The thyroid gland was dissected and fixed immediately in 10% formalin saline. The assessment of thyroid structure was based on hematoxylin and eosin, and Masson's trichrome stainings, and histomorphometric analysis of the deparaffinized sections. Localization and distribution of vimentin and cytokeratin filaments was assessed by immunohistochemistry. Measurements of VEGF gene expression by qPCR and oxidative/antioxidative markers (malondialdehyde and glutathione content, superoxide dismutase activity) in thyroid gland homogenates were performed. Serum concentration of thyroid hormones (T3, T4) and TSH were assessed by radioimmunoassay. RESULTS: Follicles in the late adult control group were dilated and disrupted. Follicular cells showed cytoplasmic vacuolation. Follicles in the thyroids of senile rats were of irregular shape, often with cellular exfoliations. Many follicles were dilated and lined with flattened cells. A notable amelioration of these morphological alterations was observed in late adult NS-treated rats. Decrease in serum T3 and T4 levels and increase in TSH levels were observed in the late adult control and senile groups. A clear shift of the oxidative/antioxidative markers (MDA/ /GSH, SOD) was observed in the late adult control and senile groups in favor of oxidants. Administration of NS to late adult rats resulted in normalization of these parameters. Increased area of collagen fibers, immunoreactivity of vimentin and cytokeratin filaments and VEGF gene expression were observed in the thyroids of late adult and senile rat groups as compared to young animals. The mean number of follicular cells decreased in the late adult control and senile groups. Administration of NS to the late adult rats returned these parameters to the level of the young adult rats. CONCLUSIONS: Aging-related alterations in both structure and function of the rat thyroid gland that are associated with increased indices of oxidative stress might be abrogated by administration of antioxidative agents present in Nigella sativa oil.

Protective Role of N-Acetylcysteine on Isoprenaline-Induced Myocardial Injury: Histological, Immunohistochemical and Morphometric Study.

Several researchers studied the protective effect of the N-acetylcysteine (NAC) when it was given before the induction of myocardial infarction (MI). Other researchers studied such protective effect when it was before done and after done of the MI. The missing data are the comparison between the protective effect of NAC before myocardial injury with its protective effect both before and after myocardial injury. The aim of the study was to compare the cardioprotective effect of NAC on the isoprenaline-induced myocardial injury before the isoprenaline (ISP) injection with its protective effect both before and after the ISP injection. This study was applied over both short and long time periods. A total of 90 male adult Wistar albino rats were used in the study. The rats were divided into four groups: control group, ISP-treated group, NAC-pretreated group and NAC-pre-& posttreated group. Based on the duration of the experiment, the second and third groups were further subdivided into a and b groups. Histological, immunohistochemical and histomorphometric analysis were used. The myocytes in the ISP-treated groups were fragmented, disrupted with karyolysis. The blood vessels were dilated, congested and associated with blood extravasation, interstitial edema and cellular inflammatory infiltration. Much improvement was observed in the NAC-pretreated group. Focal degeneration was detected in the muscle fibers. The capillaries were normal. Minimal blood extravasation and cellular infiltration were seen. The cardiac muscle fibers in the NAC-pre-& posttreated group were regularly arranged. The mean collagen fiber area percent of the ISP-treated groups was significantly higher by 8.3-folds and 10.1-folds as compared with that of the control group and was also higher by 5.5-folds and 6.8-folds as compared with that of the NAC-pre-&posttreated groups. The α-SMA area percent in the ISP-treated groups was significantly higher by 12.2-folds and 23.9-folds as compared with that of the control group and was higher by 7.5-folds and 15-folds as compared with that of the NAC-pre-& posttreated groups. The mean PCNA area percent of the ISP-treated groups was significantly higher by 126.2 and 164.8% as compared with that of the control group and was higher by 106.3 and 141.5% as compared with that of NAC-pre-& posttreated groups. ISP had deleterious effects on the heart. Administration of NAC before ISP injection could largely reduce the ISP-induced short- and long-term alterations. The protection was maximum with the use of NAC before the ISP injection and continued after the injection for 12 days.